The present invention relates to novel media in the form of complex dispersions, to their process of preparation and to their uses.
Various approaches have been used to gradually release active principles by resorting to structured media.
Emulsions are the simplest structured media, with compartments, for example oily compartments, dispersed in an aqueous continuous medium (‘direct’ or O/W emulsion, the opposite case, water-in-oil, being known as an inverse or W1/O emulsion). However, these systems, although they are widely used, do not make it possible to separate two media of the same nature, such as a hydrophilic solute which it may be desired to disperse in an aqueous continuous medium while preventing it from dissolving in this continuous medium.
This disadvantage has been circumvented by the use of multiple emulsions consisting of a first emulsion, for example an inverse W1/o emulsion, of droplets of water in an oily medium, itself emulsified in an aqueous medium W2. A W1/O/W2 emulsion is thus obtained in which a solute of the internal aqueous medium W1 is theoretically separated from the continuous medium W2 and therefore does not dissolve therein. The opposite case O1/W/O2 is obviously also possible. For a review of multiple emulsions and their preparation, reference may be made to one of the following documents: S. Matsumoto et al., ‘Formation and Application of Multiple Emulsions’, J. Dispersion Science and Technology, 10, 455-482 (1989), or C. Prybilsky et al., ‘W/O/W Multiple Emulsions: Manufacturing and Formulation Considerations’, Cosmetics and Toiletries, 106, 143-150 (1994). Many patents relate to the preparation and in particular the stabilization of multiple emulsions, and to their applications in cosmetics. Mention will be made, in the case of W/O/W emulsions, of: GB 1 541 463 (LION Dentifrice Co.), WO 95/7155 (Beierdsdorf), WO 9422414 (Henkel), FR 9302795 (Roussel-Uclaf) EP 0 731 685 (IFAC), EP 0 692 957 (Goldschmidt), U.S. Pat. No. 5,478,561 (Lancaster) and EP 92915365 (Emory Univ.). These documents only represent a sample of the many patents in the field, restricted mainly to cosmetics and to pharmaceuticals.
All these documents present conventional processes for the preparation of emulsions, starting from an aqueous phase emulsified in an oil medium using various surfactants. This first emulsion is subsequently itself emulsified in an aqueous continuous medium. The methods for preparing the first emulsion are conventional methods which can be classified into three main methods: mechanical dispersion, phase inversion and spontaneous emulsification. The document EP 92915365 (Emory Univ.) accurately describes these various methods, and gives several general references. In principle, all the methods use, for the emulsification of the water W1 (internal phase) in the oil, a surfactant of low HLB, typically less than 8, generally of nonionic nature. On the other hand, the emulsion of the W1/O system in W2 uses a surfactant of high HLB which can be nonionic or ionic. Many additives have been described and their use patented in attempting to stabilize these complex systems. The main difficulty arises from the low stability of the W1/O emulsion and from the tendency of the surfactant used for the second emulsion to destabilize the first. Mention may be made, among the most widely used additives, of sugars (cf. GB 1 541 463) and polymers, intended for example to gel the aqueous phase (cf. FR 9302795). Moreover, several examples are found in the literature of the use of polymer surfactants which clearly stabilize multiple emulsions (cf., for example, GB 1 541 463, which uses Pluronic®, U.S. Pat. No. 5,478,561, which uses polyglycerol esters, or WO 9422414, which uses polyalkylene derivatives).
Many documents are found in the literature which describe media in which an active principle is found encapsulated within vesicles, known as lamellar vesicles, comprising at least one bilayer of surfactants. These vesicles are often denoted by unilamellar, paucilamellar or multilamellar vesicles, according to whether they comprise one, a limited number or a large number of bilayers. Liposomes and niosomes® are examples of surfactant-based lamellar vesicles.
Multilamellar vesicles include those, hereinafter denoted by vesicles with an onion structure, which are vesicles with an essentially spherical shape composed of a uniform sequence of concentric bilayers, from the −20 center to the periphery of the vesicles.
Such vesicles are clearly distinguished from conventional multilamellar liposomes by the uniformity of the stacking of the surfactant bilayers from which they are formed. The uniformity of this stacking results from the thermodynamic nature of the vesicles and from their liquid crystal symmetry.
These structures can be demonstrated by microscopic examination of the compositions. Observation is carried out using a polarized-light optical microscope, in which a birefringent lamellar phase is visible. It is expressed by a characteristic texture, related to the presence of defects (grain boundaries) between phase domains oriented in different directions. In the case of the concentrated vesicle phase, the texture is characterized by its uniform and fine nature, related to the size of the vesicles. In the dispersed vesicle phase, the vesicles are visible in the form of slightly birefringent points which are more or less resolved (according to the size). Birefringence is only observed when the dispersion is not too dilute or when the vesicles are sufficiently large (typically with a diameter of greater than 5 μm). Therefore, if the dispersion is relatively dilute, there will be grounds for carrying out a preliminary concentrating operation in order to clearly demonstrate the birefringence characteristic of the presence of these vesicles.
Such vesicles can be obtained by conversion of a lamellar liquid crystal phase incorporating at least one surfactant under the effect of shearing. Examples of the preparation and use of such multilamellar vesicles are given in particular in International Applications WO 93/19735, WO 95/18601, WO 95/19707, WO 97/00623 and WO 98/02144.
Multilamellar vesicles comprising surfactants, in particular vesicles with an onion structure, are systems which can encapsulate or incorporate active principles, creating an internal medium, different from the external medium, within which the active principles are retained. The retention of the active principle inside the vesicle has two causes:                Thermodynamic: the difference in affinity of the active principle between the external medium and the internal medium results in its partition between the two media. For this reason, in the example of an aqueous dispersion of the vesicles, an amphiphilic active principle will be preferentially localized within the vesicles, whereas a very hydrophilic active principle will be localized instead in the external medium and will thus be only very weakly encapsulated.        Kinetic: each surfactant-based membrane forms a diffusion barrier which slows down the passage and thus the escape of the active principle toward the outside. This mechanism is all the more effective as the active principle is a large molecule, the diffusion coefficient of which will be low.        
It will thus be noted, quite obviously, that a small and very hydrophilic molecule will not be, or will only be very slightly, encapsulated in the vesicles, since its affinity will give it a preference for the external medium (still assuming a dispersion of the vesicles in an aqueous medium) and since the barriers formed by the surfactant bilayers will only be slightly effective in retaining it. A small or large molecule is understood to mean a molecule with a molar mass respectively of less than 500 or greater than 1000 g/mol. The same reasoning holds for the encapsulation of a very lipophilic molecule when the vesicles are dispersed in an oily medium.
In the same way, and to an even more marked extent, the same mechanisms are involved during the encapsulation of molecules in conventional liposomes, which are vesicles formed from a small number of bilayers throughout an aqueous core (or several) aqueous cores.
In this case, first, the medium of the aqueous core is very similar to the external medium and thus the difference in affinity of the encapsulated active principle will be very low, and, secondly, the low number of membranes implies an overall diffusion barrier which is much less effective.
There is also a technical need to improve encapsulation systems based on surfactant membranes in order, in particular, to confer better leaktightness thereon. In fact, there is little scope for possible adjustment with respect to the thermodynamic parameter, apart from the specific choice of surfactants. However, when a product is soluble in water, the modification of the surfactant may make virtually no improvement to its coefficient of partition between the water of the external phase and the interior of the vesicle. Furthermore, the external medium is often a complex medium itself comprising surfactants (the case of emulsions or shampoos) or other components (polymers, electrolytes, and the like) capable of increasing the affinity of the active principle for this medium and thus of further disadvantaging its coefficient of partition with the outside.
The only effective means a priori is thus to vary the kinetics of escape. To do this, the leaktightness of the barriers can be modified, for example by changing surfactants, or this leaktightness can be reinforced by incorporation of a polymer in the membranes or in the aqueous layers. This method encounters difficulties of a practical nature (the surfactants which can be used to form the membranes all have fairly similar diffusion properties) but also theoretical difficulties: the introduction of a polymer into a layer with a thickness of a few manometers introduces, in many cases, only a relatively ineffective diffusion barrier, the polymer layer being virtually monomolecular.
Another method consists in coating the vesicle in a ‘shell’ of polymer via a conventional method of encapsulation by polymer, such as, for example, coacervation. This method, while attractive, exhibits several difficulties, first with regard to its implementation and secondly with regard to the characteristics of the objects obtained. Vesicles made of surfactant membranes generally have sizes in the region of a micrometer, whereas capsules obtained by coacervation have diameters of between several tens of and several hundred micrometers. Furthermore, coacervation is usually carried out using an emulsion, the polymer or polymers during their ‘insolubilization’ being adsorbed at the interface between the oil and the water around each droplet of the emulsion. It is not certain that the adsorption of the polymer is possible or at least effective at the interface between the water and the external surfactant layer of the vesicles. Coacervation techniques are thus not entirely suited to the coating of surfactant-based vesicles. Furthermore, the objects obtained by this technique are microcapsules which have to be ruptured to release the active principle, in contrast to vesicles, which release their active principle slowly by diffusion. To coat the vesicles with a polymer shell will thus profoundly change the nature of the vesicles and in particular their destination and their use. It is the same for other techniques for coating by polymer, such as atomization.